Pradip De, PhD, MS
Rapid progress in the use of genomic tests via NGS, including targeted gene panels, whole-exome sequencing (WES), and whole-genome sequencing (WGS), in research and clinical trials provides an opportunity to identify the molecular features of cancers. These molecular alteration-based targeted therapeutics have led to the development and approval of personalized interventions for various malignancies. In the last decade, histology-independent targetable molecular alteration has been a critical development in targetable drug approval in various solid tumors. Basket trials are a type of master protocol that studies the activity of a single drug in patients with different malignancies but shares the same genetic alterations. Genomics is pouring a new era of histology/tumor-agnostic therapies for cancer in which drugs are approved for biomarkers (gene alteration) rather than types of malignancies.
Increasing evidence showed that the molecular aberrations in a tumor are the drivers of oncogenic growth rather than the organ site of origin, hence the high response rates seen with current tissue-agnostic approvals. The drawback to tissue-agnostic approvals is that there may be a possibility that the approved drugs do not work at the same level due to co-occurring alterations and their impact on response in different organ sites.
The genomically driven, tissue-agnostic approvals include therapies targeting immune system abnormalities and aberrant genes. As of December 2023, there are six different tissue-agnostic medicines approved for different indications within oncology:
· Pembrolizumab for patients with tumors deficient in mismatch repair (dMMR) or with high microsatellite instability (MSI).
· Larotrectinib/Entrectinib for patients with NTRK-fusions-positive tumors.
· Pembrolizumab for patients affected by tumors with high tumor mutational burden (TMB).
· Dostarlimab-gxly for patients with mismatch repair deficient (dMMR) tumors.
· Dabrafenib + Trametinib in patients with BRAF V600E mutated tumors
· Selpercatinib in patients with RET fusion-positive tumors.
Several other histology-agnostic therapies are in the pipeline, with the potential to increase prospects for precision medicine in oncology. Research and clinical trials have demonstrated encouraging activities from RLY-4008 in patients with heavily pretreated HR-positive, HER2-negative breast cancer with FGFR2 alterations or in patients with cholangiocarcinoma. The eNRGy trial is evaluating the use of Zenocutuzumab in patients with NRG1 fusions. Ongoing clinical trials also investigate the efficacy of Seribantumab (NCT04383210) and Afatinib (NCT04410653) in patients with NRG1 fusion-positive tumors. Phase 2 of KRYSTAL-1 is studying the use of Adagrasib in KRAS G12C-mutated solid tumors, excluding non-small cell lung cancer (NSCLC) and colorectal cancer and PC14586 in patients with TP53 Y220C mutations.
Antibody-drug conjugates (ADCs) have additionally seen rapid development for cancer therapy. Since the FDA approval of Gemtuzumab Ozogamicin for the treatment of acute myeloid leukemia in 2000, more than a dozen ADCs have received FDA approval, and more than 300 ADCs are in clinical development, as reported from the SABC Annual Meeting in San Antonio December 5-9th, 2023. DESTINY-PanTumor02 Phase II trial showed the efficacy and safety of Trastuzumab Deruxtecan in Patients with HER2-expressing solid tumors (Meric-Bernstam et al., 2024). TROP-2 ADC Sacizutumab Govitecan has been approved in a variety of malignancies, including in pretreated HR+/HER2- metastatic breast cancer, the first-line treatment for metastatic Triple-Negative Breast Cancer (TNBC), for the treatment of metastatic urothelial cancer and progress in clinical study in patients with ovarian cancer.
The European Medicine Agency (EMA) has also authorized a few of these agents — for example, the NTRK inhibitors Larotrectinib and Entrectinib for NTRK fusion-bearing cancers as tissue-agnostic indications (Adashek et al., 2023). In contrast to the situation for solid cancers, there is currently only one tissue-agnostic FDA approval for hematological malignancies, which is for Pemigatinib (an FGFR1, FGFR2, and FGFR3 inhibitor) in adults with FGFR1-rearranged relapsed myeloid/lymphoid neoplasms, based on a complete cytogenetic response rate of >70% (Freyer et al., 2023).
With rapidly changing drug approvals, VieCure is equipped to support clinicians utilizing these drugs within practice. Rules are embedded within the platform to optimize the most effective targeted treatments and immunotherapies based on the molecular profile of the tumor based on genomic and/or tumor presentation. Assessments are available to monitor and manage potential toxicities or side effects. Plans are equipped to manage treatment including lab monitoring, supportive care agents, and toxicity management. These targeted treatments and immunotherapies based on the molecular profile of the tumor are critical to the progress of cancer treatment as they provide personalized care.
Meric-Bernstam, F., Makker, V., Oaknin, A., Oh, D.Y., Banerjee, S., Gonzalez-Martin, A., Jung, K.H., Lugowska, I., Manso, L., Manzano, A., et al. (2024). Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. Journal of Clinical Oncology, 42, 47-58.
Adashek, J. J., Kato, S., Sicklick, J. K., Lippman, S. M., & Kurzrock, R. (2023). Considering molecular alterations as pan-cancer tissue-agnostic targets. Nature cancer, 4(12), 1622–1626. https://doi.org/10.1038/s43018-023-00676-y
Freyer, C. W., Hughes, M. E., Carulli, A., Bagg, A., & Hexner, E. (2023). Pemigatinib for the treatment of myeloid/lymphoid neoplasms with FGFR1 rearrangement. Expert review of anticancer therapy, 23(4), 351–359. https://doi.org/10.1080/14737140.2023.2192930
Pradip De, PhD, MS
Signal Transduction Pathway Consultant – Viecure, Assistant Professor, Department of Internal Medicine at the University of South Dakota, South Dakota, USA